id: P54803
gene_symbol: GALC
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: GALC (galactocerebrosidase / galactosylceramidase; EC 3.2.1.46) is a lysosomal
  glycoside hydrolase of the GH59 family that catabolizes galactolipids. It hydrolyzes the
  terminal galactose from galactosylceramide (galactocerebroside) to yield ceramide plus
  D-galactose, and also hydrolyzes galactosylsphingosine (psychosine) and related
  galactolipids. Acting at acidic pH in the lysosome/lysosomal lumen, the soluble enzyme
  depends on the lipid-transfer protein saposin A (derived from prosaposin, PSAP), which
  presents the membrane-embedded glycosphingolipid substrate to the GALC active site.
  Galactosylceramide is a major lipid of the myelin sheath, so GALC is central to myelin
  glycosphingolipid turnover. Loss of GALC activity causes Krabbe disease (globoid cell
  leukodystrophy), an autosomal recessive lysosomal storage disorder in which accumulation
  of the cytotoxic substrate psychosine drives demyelination and neurodegeneration.
alternative_products:
- name: '1'
  id: P54803-1
- name: '3'
  id: P54803-3
  sequence_note: VSP_036976
- name: '4'
  id: P54803-4
  sequence_note: VSP_036974
- name: '5'
  id: P54803-5
  sequence_note: VSP_036975, VSP_036977
existing_annotations:
- term:
    id: GO:0004336
    label: galactosylceramidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (PAN-GO) transfer of the defining molecular function of GALC.
      GALC is a GH59 galactosylceramidase (EC 3.2.1.46) that hydrolyzes the terminal
      galactose from galactosylceramide; this is the biochemically demonstrated core
      activity of the human enzyme.
    action: ACCEPT
    reason: This is the correct, specific molecular function for GALC and represents its
      core catalytic activity. It is directly supported by biochemistry on the purified
      human enzyme and cDNA expression, and is consistent across the phylogenetic tree.
    supported_by:
      - reference_id: PMID:8399327
        supporting_text: "Galactocerebrosidase (GALC, EC 3.2.1.46) was purified from human urine"
      - reference_id: file:human/GALC/GALC-uniprot.txt
        supporting_text: "Hydrolyzes the galactose ester bonds of glycolipids such as"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic transfer of lysosomal localization. GALC is a soluble acid
      hydrolase that acts in the lysosome; UniProt subcellular location is Lysosome and the
      enzyme has an acidic pH optimum consistent with lysosomal function.
    action: ACCEPT
    reason: Lysosome is the correct site of action for GALC and is well supported. Retained
      as a core localization for this lysosomal enzyme.
    supported_by:
      - reference_id: PMID:8281145
        supporting_text: "responsible for the lysosomal catabolism of galactosylceramide, a major lipid in"
      - reference_id: PMID:7601472
        supporting_text: "catalyzes the lysosomal hydrolysis of specific galactolipids"
- term:
    id: GO:0006683
    label: galactosylceramide catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic transfer of the core biological process. By hydrolyzing
      galactosylceramide to ceramide and galactose, GALC executes the lysosomal
      galactosylceramide catabolic process.
    action: ACCEPT
    reason: This is the precise biological process for GALC's catalytic activity and is its
      core role. Retained as a core function.
    supported_by:
      - reference_id: PMID:8281145
        supporting_text: "responsible for the lysosomal catabolism of galactosylceramide, a major lipid in"
      - reference_id: PMID:15657896
        supporting_text: "galactosylcerebroside to ceramide"
- term:
    id: GO:0004336
    label: galactosylceramidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated (ARBA/InterPro/RHEA/EC) assignment of galactosylceramidase activity,
      mapping GALC (GH59 family, EC 3.2.1.46, RHEA:14297) to its defining molecular function.
    action: ACCEPT
    reason: The electronic mapping is correct and matches the experimentally verified core
      activity; the same term is independently supported by IDA and IBA.
    supported_by:
      - reference_id: file:human/GALC/GALC-uniprot.txt
        supporting_text: "Belongs to the glycosyl hydrolase 59 family"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt SubCellular-location keyword mapping to lysosome, consistent with the
      curated UniProt subcellular location (Lysosome) for this acid hydrolase.
    action: ACCEPT
    reason: Lysosomal localization is correct and independently supported (IBA, TAS). Kept
      as a core localization.
    supported_by:
      - reference_id: PMID:7601472
        supporting_text: "catalyzes the lysosomal hydrolysis of specific galactolipids"
- term:
    id: GO:0006683
    label: galactosylceramide catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Automated (ARBA/InterPro) assignment of galactosylceramide catabolic process,
      the precise biological process executed by GALC's hydrolase activity.
    action: ACCEPT
    reason: Correct electronic mapping matching the experimentally supported core process;
      also supported by IDA, IBA and ISS.
    supported_by:
      - reference_id: PMID:8281145
        supporting_text: "responsible for the lysosomal catabolism of galactosylceramide, a major lipid in"
- term:
    id: GO:0006683
    label: galactosylceramide catabolic process
  evidence_type: IDA
  original_reference_id: PMID:15657896
  qualifier: involved_in
  review:
    summary: Galactosylceramide catabolic process supported by a review of GALC/GalCer
      metabolism in cancer, which describes GALC as the enzyme degrading galactosylcerebroside
      to ceramide. The biology (GALC breaks down galactosylceramide) is correct.
    action: ACCEPT
    reason: The annotated process is the correct core process for GALC. The cited reference
      is a review (annotated IDA), so it is not the strongest primary evidence, but the same
      process is robustly supported by primary biochemistry (PMID:8281145, PMID:8399327) and
      by IBA. Per curation policy, the experimental annotation is retained rather than removed.
    supported_by:
      - reference_id: PMID:15657896
        supporting_text: "the enzyme responsible for degrading"
      - reference_id: PMID:15657896
        supporting_text: "galactosylcerebroside to ceramide"
- term:
    id: GO:0004336
    label: galactosylceramidase activity
  evidence_type: IDA
  original_reference_id: PMID:8281145
  qualifier: enables
  review:
    summary: Direct assay of galactosylceramidase activity. The human GALC cDNA was cloned
      and expressed in COS-1 cells, yielding GALC enzyme activity; the enzyme is defined as
      responsible for lysosomal catabolism of galactosylceramide. This is the primary
      experimental basis for the core molecular function.
    action: ACCEPT
    reason: Direct experimental support (cDNA expression conferring GALC activity) for the
      core catalytic function; represents the defining molecular function of the gene.
    supported_by:
      - reference_id: PMID:8281145
        supporting_text: "responsible for the lysosomal catabolism of galactosylceramide, a major lipid in"
- term:
    id: GO:0004336
    label: galactosylceramidase activity
  evidence_type: IDA
  original_reference_id: PMID:8281145
  qualifier: enables
  review:
    summary: Direct assay of galactosylceramidase activity (duplicate GOA record from a
      different assigning group, same term/evidence/reference). Human GALC cDNA expression
      confers GALC enzyme activity, defining the core molecular function.
    action: ACCEPT
    reason: Duplicate of the direct-evidence galactosylceramidase-activity annotation; same
      correct core molecular function. Retained.
    supported_by:
      - reference_id: PMID:8281145
        supporting_text: "responsible for the lysosomal catabolism of galactosylceramide, a major lipid in"
- term:
    id: GO:0036021
    label: endolysosome lumen
  evidence_type: IC
  original_reference_id: PMID:27498570
  qualifier: is_active_in
  review:
    summary: Curator inference (IC) placing GALC's activity in the endolysosome lumen,
      derived from its acid-hydrolase molecular function (GO:0004336) together with the
      general finding that endolysosomes are the principal intracellular sites of acid
      hydrolase activity. The cited paper is a general endolysosome study and does not assay
      GALC specifically.
    action: KEEP_AS_NON_CORE
    reason: Reasonable and biologically consistent refinement of the lysosomal localization,
      but it is an inference from a general acid-hydrolase study rather than GALC-specific
      evidence. The core, best-supported localization for GALC is the lysosome/lysosomal
      lumen; kept as a non-core, more granular localization.
    supported_by:
      - reference_id: PMID:27498570
        supporting_text: "endolysosomes are the principal organelles in which substrates are hydrolyzed"
- term:
    id: GO:0036021
    label: endolysosome lumen
  evidence_type: IC
  original_reference_id: PMID:29323104
  qualifier: is_active_in
  review:
    summary: Curator inference (IC) that GALC is active in the endolysosome lumen, supported
      by the GALC-SapA complex study showing that GALC-mediated glycosphingolipid degradation
      occurs at low pH equivalent to the late-endosomal/lysosomal (endolysosomal) compartment
      and requires saposin A.
    action: KEEP_AS_NON_CORE
    reason: The endolysosomal context is well grounded in this GALC-specific structural and
      biochemical study, but at the granularity used by this project the core localization is
      the lysosome/lysosomal lumen. Retained as a non-core, more granular localization.
    supported_by:
      - reference_id: PMID:29323104
        supporting_text: "responsible for the removal of the terminal galactose from the glycosphingolipid galactocerebroside"
      - reference_id: PMID:29323104
        supporting_text: "This enzyme requires the saposin SapA for lipid"
- term:
    id: GO:0046479
    label: glycosphingolipid catabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840310
  qualifier: involved_in
  review:
    summary: Reactome pathway annotation placing GALC in glycosphingolipid catabolism.
      Galactosylceramide is a glycosphingolipid, so this is a correct but broader-than-precise
      parent process relative to galactosylceramide catabolic process.
    action: KEEP_AS_NON_CORE
    reason: Correct but more general than the precise core term (GO:0006683 galactosylceramide
      catabolic process). Retained as a valid non-core, higher-level pathway annotation.
    supported_by:
      - reference_id: PMID:29323104
        supporting_text: "responsible for the removal of the terminal galactose from the glycosphingolipid galactocerebroside"
- term:
    id: GO:0030149
    label: sphingolipid catabolic process
  evidence_type: IDA
  original_reference_id: PMID:8281145
  qualifier: involved_in
  review:
    summary: Sphingolipid catabolic process, a broad parent of the precise galactosylceramide
      catabolic process. GALC catabolizes galactosylceramide (a glycosphingolipid) and
      galactosylsphingosine, so it acts in sphingolipid catabolism.
    action: KEEP_AS_NON_CORE
    reason: Correct but less specific than the core term (GO:0006683 galactosylceramide
      catabolic process). Retained as a valid non-core, higher-level process annotation.
    supported_by:
      - reference_id: PMID:8281145
        supporting_text: "responsible for the lysosomal catabolism of galactosylceramide, a major lipid in"
- term:
    id: GO:0004336
    label: galactosylceramidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1606564
  qualifier: enables
  review:
    summary: Reactome traceable assertion of galactosylceramidase activity (reaction "GALC
      hydrolyzes GalCer"), matching the defining, experimentally verified core molecular
      function of GALC.
    action: ACCEPT
    reason: Correct core molecular function, independently supported by IDA and IBA. Retained
      as core.
    supported_by:
      - reference_id: PMID:8399327
        supporting_text: "Galactocerebrosidase (GALC, EC 3.2.1.46) was purified from human urine"
- term:
    id: GO:0004336
    label: galactosylceramidase activity
  evidence_type: IDA
  original_reference_id: PMID:8399327
  qualifier: enables
  review:
    summary: Direct biochemical characterization of galactosylceramidase activity. GALC
      (EC 3.2.1.46) was purified ~176,000-fold from human urine (and brain, placenta) with
      an acidic pH optimum (4.0-4.4) and KM=10 uM for N-acyl-beta-D-galactosylsphingosine,
      directly demonstrating the enzyme's activity.
    action: ACCEPT
    reason: Strong direct experimental evidence for the core molecular function of GALC on
      the purified human enzyme. Retained as core.
    supported_by:
      - reference_id: PMID:8399327
        supporting_text: "Galactocerebrosidase (GALC, EC 3.2.1.46) was purified from human urine"
- term:
    id: GO:0006683
    label: galactosylceramide catabolic process
  evidence_type: IDA
  original_reference_id: PMID:8399327
  qualifier: involved_in
  review:
    summary: Galactosylceramide catabolic process supported by direct characterization of the
      purified human enzyme, which is deficient in Krabbe disease and cleaves galactolipid
      substrates. This is the precise core biological process for GALC.
    action: ACCEPT
    reason: Direct experimental support for the core catabolic process of GALC. Retained as
      core.
    supported_by:
      - reference_id: PMID:8399327
        supporting_text: "Galactocerebrosidase (GALC, EC 3.2.1.46) was purified from human urine"
- term:
    id: GO:0004336
    label: galactosylceramidase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity transfer of galactosylceramidase activity from the mouse
      ortholog (UniProtKB:P54818). GALC is a conserved GH59 galactosylceramidase.
    action: ACCEPT
    reason: The ortholog-based transfer is correct and redundant with the direct
      experimental (IDA) and IBA support for the same core molecular function.
    supported_by:
      - reference_id: file:human/GALC/GALC-uniprot.txt
        supporting_text: "Belongs to the glycosyl hydrolase 59 family"
- term:
    id: GO:0006683
    label: galactosylceramide catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity transfer of galactosylceramide catabolic process from the
      mouse ortholog (UniProtKB:P54818), matching GALC's precise core biological process.
    action: ACCEPT
    reason: Correct ortholog-based transfer, redundant with direct (IDA) and IBA support for
      the same core process.
    supported_by:
      - reference_id: PMID:8281145
        supporting_text: "responsible for the lysosomal catabolism of galactosylceramide, a major lipid in"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1606564
  qualifier: located_in
  review:
    summary: Reactome traceable assertion localizing GALC to the lysosomal lumen, the
      compartment where the soluble acid hydrolase acts on its substrate.
    action: ACCEPT
    reason: Correct and specific localization of this soluble lysosomal hydrolase to the
      lysosomal lumen. Retained as a core localization.
    supported_by:
      - reference_id: PMID:7601472
        supporting_text: "catalyzes the lysosomal hydrolysis of specific galactolipids"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: TAS
  original_reference_id: PMID:7601472
  qualifier: located_in
  review:
    summary: Lysosome localization asserted from the literature. The GALC gene-structure
      paper describes the enzyme as catalyzing lysosomal hydrolysis of galactolipids,
      consistent with a lysosomal acid hydrolase.
    action: ACCEPT
    reason: Correct core localization, independently supported by IBA and Reactome TAS.
      Retained as core.
    supported_by:
      - reference_id: PMID:7601472
        supporting_text: "catalyzes the lysosomal hydrolysis of specific galactolipids"
core_functions:
- description: >-
    Lysosomal galactosylceramidase (galactocerebrosidase, EC 3.2.1.46): a soluble GH59
    acid hydrolase that removes the terminal galactose from galactosylceramide
    (galactocerebroside) to yield ceramide and D-galactose, and also hydrolyzes
    galactosylsphingosine (psychosine) and related galactolipids. It thereby carries out the
    lysosomal galactosylceramide catabolic step of glycosphingolipid degradation, acting on
    membrane-embedded substrate presented by saposin A (from PSAP). Galactosylceramide is a
    major myelin lipid, and loss of this activity causes Krabbe disease (globoid cell
    leukodystrophy).
  molecular_function:
    id: GO:0004336
    label: galactosylceramidase activity
  directly_involved_in:
  - id: GO:0006683
    label: galactosylceramide catabolic process
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  - id: GO:0005764
    label: lysosome
  supported_by:
  - reference_id: PMID:8399327
    supporting_text: "Galactocerebrosidase (GALC, EC 3.2.1.46) was purified from human urine"
  - reference_id: PMID:8281145
    supporting_text: "responsible for the lysosomal catabolism of galactosylceramide, a major lipid in"
  - reference_id: PMID:7601472
    supporting_text: "catalyzes the lysosomal hydrolysis of specific galactolipids"
  - reference_id: PMID:29323104
    supporting_text: "This enzyme requires the saposin SapA for lipid"
  - reference_id: file:human/GALC/GALC-uniprot.txt
    supporting_text: "Hydrolyzes the galactose ester bonds of glycolipids such as"
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15657896
  title: Implications of galactocerebrosidase and galactosylcerebroside metabolism
    in cancer cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified review describing GALC as the enzyme degrading
      galactosylcerebroside to ceramide. Correctly supports the catabolic role but is a
      review (used as IDA in GOA), so it corroborates rather than establishes the core
      function.
- id: PMID:27498570
  title: Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase Activity.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified general study establishing that endolysosomes are the
      principal sites of acid hydrolase activity. It does not assay GALC; it underpins the
      curator (IC) inference for GALC's endolysosome-lumen localization only indirectly.
- id: PMID:29323104
  title: The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex
    structure.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. GALC-SapA complex structure defining the saposin-A
      dependent mechanism of galactocerebroside cleavage in the endolysosomal compartment.
      Directly relevant to GALC's mechanism and localization.
- id: PMID:7601472
  title: Structure and organization of the human galactocerebrosidase (GALC) gene.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Gene-structure paper that also states GALC catalyzes
      lysosomal hydrolysis of galactolipids including galactosylceramide and
      galactosylsphingosine (psychosine); supports catalytic function and lysosomal
      localization.
- id: PMID:8281145
  title: Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme
    deficient in globoid cell leukodystrophy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified primary paper cloning and expressing human GALC cDNA;
      establishes GALC as responsible for lysosomal catabolism of galactosylceramide.
- id: PMID:8399327
  title: 'Galactocerebrosidase from human urine: purification and partial characterization.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified primary biochemistry; purification and enzymatic
      characterization of human GALC (EC 3.2.1.46), including acid pH optimum and KM.
      Direct support for the core molecular function.
- id: Reactome:R-HSA-1606564
  title: GALC hydrolyzes GalCer
  findings: []
- id: Reactome:R-HSA-9840310
  title: Glycosphingolipid catabolism
  findings: []
- id: file:human/GALC/GALC-uniprot.txt
  title: UniProtKB P54803 (GALC_HUMAN) record
  findings: []